Key Issue: Standards for Radioactive Articles in USP-NF

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July 31, 2015:

The scope of this Key Issues page is being expanded from PET drugs to cover all radioactive articles in USP.

The USP is actively working on several general chapters that are pertinent to nuclear medicine. These activities include the revision of General Chapter <821> Radioactivity, as well as the development of two new general chapters. The details of these changes are described below. Drafts of the affected General Chapters will appear in an upcoming issue of the Pharmacopeial Forum (PF) 41(5) [Sep.–Oct. 2015]. To logon or register for free access to the PF, please visit http://www.usppf.com/pf/login

Public comments on these General Chapters will be accepted until November 30, 2015. USP encourages the public to comment on these General Chapters especially from all members of the nuclear medicine and PET communities, including drug manufacturers, professional associations, and regulatory agencies.

<821> Radioactivity: This General Chapter was introduced in its current form in 1975 and has not undergone any major revision since its first publication. Currently, the General Chapter contains definitions, special considerations, and procedures with respect to the monographs for radiopharmaceuticals (radioactive drugs). The majority of this General Chapter, however, is nonprocedural. Because USP has launched an initiative to minimize nonprocedural information in general chapters numbered below 1000, the USP Council of Experts has decided to revise <821> as part of this initiative. To achieve this objective, several members of the USP Council of Experts jointly published a Stimuli article in PF 38(4) [Jul.–Aug. 2012], Revision of General Chapter Radioactivity <821>. The purpose of the Stimuli article was threefold: (1) provide background information on the need for the proposed revision, (2) initiate discussion about this topic, and (3) solicit public comments for review and discussion by the relevant Expert Committee and Expert Panel members and USP staff in advance of revision to <821>. Based on the recommendations described in the Stimuli article and comments received, nonprocedural information is being proposed for removal from <821> and placement in a new informational General Chapter, <1821>, which is described below. The remaining content in <821> is intended to provide procedures and standards for instrumentation used in the identification and assay of radionuclides, including calibration and maintenance of instrumentation. In addition, quantitative requirements have been added for minimum detector resolution, variations in instrument performance, the appropriate interval for performance checks, and other parameters. The proposed revision can be accessed from the link below:

<1821> Radioactivity—Theory and Practice: This is a proposed new General Chapter that contains content originally in <821> Radioactivity that is related to the theory and practice of radioactivity measurements. This General Chapter describes the types of radioactive decay and the radioactive emissions, the use of radioactive standards for instrument qualification and calibration, and instrumentation for detection and measurement of radioactive emissions. In addition, a glossary has been added for common terms to reflect current practices. The proposed new General Chapter <821> can be accessed from the link below:

<1823> Positron Emission Tomography Drugs—Information: Until 2011, USP had two General Chapters related to positron emission tomography (PET) drugs. The first was <1015> Automated Radiochemical Synthesis Apparatus. This General Chapter described a quality assurance (QA) program for equipment, reagents, documentation, and software used in the production of PET drugs. The second was <823> Positron Emission Tomography for Compounding, Investigational, and Research Uses. This General Chapter provided requirements for an extensive quality assurance program for compounding PET drugs. In 2009 the U.S. Food and Drug Administration (FDA) issued a guidance document on PET drug manufacturing in which the standards in General Chapter <823> as published in USP 32–NF 27 were recognized as an alternative for current good manufacturing practice (cGMP) for investigational and research PET drugs. In 2011, General Chapter <823> was revised in its entirety to align with these changes and to represent current compendial thinking about the preparation of PET drugs. During the revision of <823>, the need for a new General Chapter to provide additional information on concepts, technologies, and procedures related to PET drug manufacturing and controls to supplement <823> was recognized by the General Chapters—Physical Analysis Expert Committee (GC–PA). The resulting new proposed General Chapter is <1823> Positron Emission Tomography Drugs—Information, which includes relevant information regarding PET radionuclides, definitions of common terminology, production and quality assurance, and quality attributes for PET drug needs of patients, research subjects, medical institutions, clinical researchers, and all members of the PET community. The inclusion of the new General Chapter <1823> would eliminate the need for General Chapter <1015>, which will be proposed for omission from the USP–NF. The proposed new General Chapter can be accessed from the link below:

Past Updates

The Second Supplement to USP 37-NF 32, which was published on June 1, 2014, included the omission of eight monographs for non-FDA approved PET drugs. Since the USP typically does not maintain monographs for non-FDA approved products, these changes bring USP’s approach to PET drug monographs in line with other USP monographs. It is important to note that these changes only affect monographs for non-FDA approved PET drugs. USP will continue to maintain monographs for FDA-approved PET drugs.

The changes were approved by the USP Small Molecules–4 Expert Committee, which is responsible for PET drugs. The Committee followed the recommendations of the Society of Nuclear Medicine and Molecular Imaging (SNMMI) Committee on Pharmacopeia (see: Journal of Nuclear Medicine, 2013, vol. 54, no. 3, pp 472-475). The article can be accessed here.

The omission of monographs for non-FDA approved PET drugs becomes official on December 1, 2014. This is the final step in a series of USP activities related to PET drug monographs. The timeline for these activities appears below:

1. SNMMI recommendations to omit monographs for non-FDA approved PET drugs published in March 2013.

2. Omission of monographs for non-FDA approved PET drugs proposed in Pharmacopeial Forum 39(4) [Jul-Aug 2013]. Public comments on this proposal were received until September 30, 2013. There were no comments opposed to the proposed omissions.

4. The omission of monographs for non-FDA approved PET drugs becomes official on December 1, 2014.

April 26, 2013

An article recently published by the Committee on Pharmacopeia associated with the Society of Nuclear Medicine and Molecular Imaging (SNMMI) describes the impact of potential changes to the role of USP monographs for PET drugs after the sunset of the 1997 FDA Modernization Act requirements for PET drugs. In addition, the article contains recommendations for USP monographs for PET drugs that are currently not approved by the FDA. The article appears in the March issue (JNM, vol. 54, no 3, pp 472-475), and can be accessed here.

October 26, 2012

The U.S. Pharmacopeial Convention (USP) is announcing the adoption of the revision of General Chapter <823> Radiopharmaceuticals for Positron Emission Tomography (PET)–Compounding in USP 35–NF 30, became official on May 1, 2012. The USP 35–NF 30 commentary, which is a summary of all the comments along with their disposition, can be found on the USP web site (commentary for <823> starts on page 8 of USP 35–NF Commentary.

USP has submitted a Citizen Petition to FDA to update the compendial reference to USP 35-NF 30 in the federal regulations on current good manufacturing practice (cGMP) for PET drugs (21 CFR § 212.5(b)).

September 1, 2011

The U.S. Pharmacopeial Convention (USP) is announcing the adoption of the revision of General Chapter <823> Radiopharmaceuticals for Positron Emission Tomography (PET)-Compounding in USP 35–NF 30, which will be published in November 2011 and official on May 1, 2012. Once the official date is reached, the title of <823> will change to "Positron Emission Tomography Drugs for Compounding, Investigational, and Research Uses". The proposal was published in Pharmacopeial Forum (PF) 37(1)[Jan–Feb 2011] for the public review and comment period, which ended on March 31, 2011. USP received several comments from industry as well as the FDA. The Drugs for Positron Emission Tomography–Compounding Expert Panel reviewed all comments and recommended subsequent changes to the text to the General Chapters–Physical Analysis Expert Committee (GCPA) and the revision was approved by GCPA. The USP 35–NF 30 commentary, which is a summary of all the comments along with their disposition, will be posted on the USP web site in November 2011, coinciding with the publication. USP has initiated the process to petition FDA to update the compendial reference to USP 35–NF 30 in its regulation. Until the reference is amended, investigational and research PET drug manufacturers will still need to comply with General Chapter <823> of USP 32–NF 27 (2009) or the Code of Federal Regulations Title 21 Part 212 to meet CGMP requirements.

March 25, 2011

On February 21, 2011 at 1:00pm EST/10:00am PST, USP hosted a live webinar where 75 participants from companies, universities and hospitals across the country shared their questions and concerns. This live event was recorded and is posted below along with the presentation slides and a document listing all the questions from the session with answers.

November 24, 2010

The U.S. Pharmacopeial Convention (USP) is seeking input on a proposed revision of General Chapter <823> Radiopharmaceuticals for Positron Emission Tomography (PET)—Compounding in the U.S. Pharmacopeia–National Formulary (USP–NF). Input is being sought from practitioners involved in PET drug production and compounding in the fields of nuclear medicine, radiology, and diagnostic imaging and related areas.

Originally published in 1998, General Chapter <823> describes requirements for the production and compounding of PET drugs, typically as injectable solutions in a multi-dose vial. Production is defined as the process of synthesis or formulation of a PET drug for investigational or research uses. Compounding is defined as the process of synthesis or formulation of a PET drug for use in pharmacy and medicine. Since the chapter's publication in 1998, technological, marketplace, and regulatory changes related to PET drugs have necessitated the chapter's revision.

In 2009, the U.S. Food and Drug Administration (FDA) published final regulations (the Final Rule) and an accompanying guidance document for PET Current Good Manufacturing Practices (CGMP). Once the FDA's Final Rule becomes effective on December 12, 2011, General Chapter <823> (as published in USP 32–NF 27) will officially constitute the minimum CGMP requirements for investigational and research PET drugs used in human subjects under an Investigational New Drug application or under the approval of a Radioactive Drug Research Committee. All other PET drugs will be subject to FDA's new CGMP requirements. It is important to note that the FDA Final Rule references General Chapter <823> in USP 32–NF 27. Once the current revision process for General Chapter <823> is completed and the chapter is published, USP will petition FDA to update the reference in its regulation. Until that is accomplished, investigational and research PET drug manufacturers will have to comply with the 1998 version of General Chapter <823> or the Code of Federal Regulations Title 21 Part 212 to meet CGMP requirements.

All comments to the revisions to Chapter <823> may be submitted to Dr. Ravi Ravichandran at USP823@usp.org by March 31, 2011.